Green Glenn (Orcid ID: 0000-0002-5156-9542) Title: 3D-printed, externally-implanted, bioresorbable airway splints for severe tracheobronchomalacia Short title: 3D-printed airway splints Authors: Andrea S. Lesa, PhD, Richard G. Ohyeb, MD, Amy G. Filbrunc, MD, Maryam Ghadimi Mahanid, MD, Colleen L. Flanagana, MS, Rodney C. Danielse, MD, Kelley M. Kidwellf, PhD, David A. Zopfa, MD, MS, Scott J. Hollisterg, PhD, Glenn E. Greena, MD Affiliations aDepartment of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI bDepartment of Cardiac Surgery, University of Michigan, Ann Arbor, MI cDepartment of Pediatric Pulmonology, University of Michigan, Ann Arbor, MI dDepartment of Radiology, University of Michigan, Ann Arbor, MI eDepartment of Pediatrics, Division of Critical Care Medicine, University of Michigan, Ann Arbor, MI fDepartment of Biostatistics, University of Michigan, Ann Arbor, MI gDepartment of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA Address correspondence to: Glenn E Green, Department of Otolaryngology-Head and Neck Surgery, Division of Pediatric Otolaryngology CW-5702 (SPC 4241) 1540 E Hospital Dr Ann Arbor, MI 48109-4241 [email protected] 734-936-4934 Presented at the Society of University Otolaryngologists meeting on 11/11/2017 in Chicago, Illinois, USA. Funding and Conflict of Interest This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/lary.27863 This article is protected by copyright. All rights reserved. This work was funded in part by the NIH under Award Number UL1TR002240, UL1TR00043, and 1U01TR002488. This work was also funded in part by NIH grants R21 HD076370 and R01 HD086201 (to S.J.H. and G.E.G.). Device development was funded by NIH grant UL1 RR024986 and FDA grant P50 FD003787. We gratefully acknowledge the support of the Michigan Institute for Clinical and Health Research (MICHR) IND/IDE Investigator Assistance Program (MIAP) for their Expanded Access regulatory support. Dr Green and Dr Hollister are co-inventors on an airway splint patent assigned to the Regents of the University of Michigan. This patent has been licensed by the University of Michigan to Materialise NV, Leuven, Belgium. The University, Dr Green, and Dr Hollister could benefit financially if and when the airway splint is commercialized. The other authors have no financial relationships relevant to this article to disclose. This article is protected by copyright. All rights reserved. Abstract Objective: To report the clinical safety and efficacy of 3D-printed, patient-specific, bioresorbable airway splints in a cohort of critically ill children with severe tracheobronchomalacia. Methods: From 2012-2018, 15 subjects received 29 splints on their trachea, right and/or left mainstem bronchi. The median age at implantation was eight months (range, 3-25 months). Nine children were female. Five subjects had a history of ECMO (extra-corporeal membrane oxygenation), and eleven required continuous sedation, six of which required paralytics to maintain adequate ventilation. Thirteen were chronically hospitalized, unable to be discharged, and seven were hospitalized their entire lives. At the time of splint implantation, one subject required ECMO, one required positive airway pressure, and 13 subjects were tracheostomy and ventilator dependent, requiring a median positive end-expiratory pressure (PEEP) of 14 cmH2O (range, 6-20 cmH20). Outcomes collected included level of respiratory support, disposition, and splint-related complications. Results: At the time of discharge from our institution, at a median of 28 days’ post-implantation (range, 10-56 days), the subject on ECMO was weaned from extracorporeal support, and the subjects who were ventilated via tracheostomy had a median change in PEEP (discharge – baseline) of -2.5 cmH2O (range, -15 to 2 cmH2O, p=0.022). At median follow-up of 8.5 months (range, 0.3-77 months), all but one of the 12 surviving subjects lives at home. Of the 11 This article is protected by copyright. All rights reserved. survivors who were tracheostomy dependent pre-op, one is decannulated, one uses a speaking valve, six use a ventilator exclusively at night, and three remain ventilator dependent. Conclusion: This case series demonstrates the initial clinical efficacy of the 3D-printed bioresorbable airway splint device in a cohort of critically ill children with severe tracheobronchomalacia. Key Words Tracheobronchomalacia, splint, 3D-printing, critical care, airway Level of Evidence: 4 This article is protected by copyright. All rights reserved. Introduction Tracheobronchomalacia is a condition of dynamic collapse of the trachea or bronchi during respiration. Diagnosis is typically made via bronchoscopy. Mild forms manifest as a cough, wheeze, or impaired secretion clearance. Severe forms have reported mortality rates up to 80% 1. Tracheobronchomalacia can be idiopathic or associated with prematurity, genetic cartilaginous or other syndromes, congenital cardiovascular anomalies, or tracheoesophageal fistulas 2,3. Current therapies for severe tracheobronchomalacia include tracheostomy with prolonged mechanical ventilation 4, aortopexy 5, tracheobronchopexy 1,6, and intraluminal metallic 7,8, silicone 9, or bioresorbable 10-12 stents. However, these options carry a significant risk of morbidity and mortality, variable efficacy, and a subset of children still suffer acute life- threatening events despite these interventions. In one study of 47 children with tracheobronchomalacia hospitalized in an intensive care setting, 28 (60%) died 3. For all but severe cases, if a child can be supported for 24 months, natural airway growth and maturation resolves symptoms 4. We have developed a 3D printed, externally implanted, bioresorbable airway splint that provides luminal support for at least two years, and is subsequently resorbed, obviating the need for surgical removal. Results of the first patient 13, and then the first three patients were reported previously 14; here we report clinical outcomes of all 15 children who received splints at our institution through July 2018. This article is protected by copyright. All rights reserved. Materials and Methods Patient Selection Only children who were at high risk of death or permanent disability were considered for airway splinting. This included life-threatening events associated with tracheobronchomalacia, mechanical ventilation requiring prolonged sedation, and airway erosion. Cross-disciplinary consultation was utilized to ensure that airway splinting did not constitute futile care. Children were not excluded for tracheobronchomalacia distal to the areas able to be splinted, severe concomitant pulmonary/cardiovascular disease, ECMO status, or underlying cartilaginous disorders. While tracheobronchomalacia is more frequently characterized by circumferential collapse due to weakness of the anterior (cartilaginous) airway, it can also be caused by intrusion of the posterior (membranous) airway. Patients were not excluded based upon type of tracheobronchomalacia. Patients with only one lung were also not excluded. Splint Design, Manufacturing Process, and Regulatory Process The splint design and fabrication process has been detailed previously 15,16. Briefly, pre-operative inspiratory/expiratory computed tomography (CT) and bronchoscopy were performed to confirm the diagnosis and location of tracheobronchomalacia. Inspiratory and expiratory patient airway models are generated from CT data using Mimics Innovation Suite (Materialise NV, Leuven, Belgium) to determine malacic segment length and diameter; splint designs are then automatically generated from this input data with Custom MATLAB (MathWorks, Natick, This article is protected by copyright. All rights reserved. Massachusetts) code, and subsequently test fit on the patient models. Splints were then 3D printed from 96% polycaprolactone/4% hydroxyapatite via laser sintering, and sterilized via ethylene oxide (Nelson Laboratories, Salt Lake City Utah). Permission from the Food and Drug Administration (FDA) and our institutional review board (IRB) was obtained for each case via the FDA Expanded Access pathway (“compassionate use”). Informed consent was obtained from each patient’s parent or guardian. Surgical Technique Pre-operative bronchoscopy is performed to evaluate the airway. A median sternotomy with or without a cervical incision is performed. The anterior and lateral aspects of the trachea and/or mainstem bronchi were isolated and the area(s) of malacia are confirmed. After choosing the splint(s) of best fit, a series of partial thickness polypropylene sutures are placed circumferentially around the malacic segment(s). The sutures were then passed through the interstices of the splint, and the splints are parachuted down on to the airways. The sutures were then tied, suspending the trachea/bronchi within the splint. Surgical clips denoted proximal and distal ends of the splints for radiographic studies. If the child required concomitant cardiac repair, this was completed after splint implantation. Intra-operative bronchoscopy confirmed patency of the splinted regions. Data Collection This article is protected by copyright. All rights reserved. For the duration of the study, parents and referring physicians were queried for clinical